The blood-brain barrier (BBB) is formed by the brain capillary endothelial cells and acts as a selective partition regulating the exchange of substances between the blood and the brain. The tight junctions of brain capillary endothelial cells prevent a majority of circulating compounds larger than 500D from reaching the brain by the paracellular route (Pardridge, 2002). Similarly, virtually no peptides, antibodies or biologics can cross the BBB in therapeutically relevant concentrations (Pardridge, 2002; Bickel et al, 2001).
There is currently no clinically approved/used approach to deliver biologics, including peptides, across the BBB after systemic injection. At present, biologics that do not cross the BBB can only be given by direct intra-cerebroventricular or intra-brain injection, by infusion through a brain-implanted pump, or by implantation of controlled-release polymers or genetically engineered cells. There are some experimental approaches that are being developed for systemic delivery of biologics, such as peptides, across the BBB including: development of highly positively charged peptides (Hervé et al, 2008); peptides functionalized with TAT-like sequences (Muriel & Dowdy, 2006); peptides that bind LRP receptor family (Demeule et al, 2008); and antibodies against receptors that undergo receptor-mediated transcytosis, such as transferrin receptor antibody and insulin receptor antibody Pardridge et al, 1991; Jones & Shusta, 2007).
Pain is a major symptom of many different diseases. Research defines different types of pain on the basis of their neuronal and molecular mechanisms into nociceptive pain (resulting from inflammation and injury) and neuropathic pain (resulting from nerve disease or injury). Pain sensation (nociception) is evoked by potential or actual noxious stimuli or by tissue injury, and is mediated by a combination of peripheral and central (brain) mechanisms. Peripheral mechanisms of pain result from noxious stimuli that produce inflammation, which excites and sensitizes ‘pain fibres’; the stimulus is transmitted through the spinal cord to the thalamocortical system in the brain where the pain sensation is given sensory discriminative aspect and affective aspect. The mediators of peripheral pain include inflammatory mediators such as prostaglandins, bradykinin, histamine, substance P, ATP, etc (Smith, 2008; Neiderberger et al, 2008). Drugs that prevent synthesis of inflammatory mediators (including non-steroidal and steroidal anti-inflammatory drugs) have analgesic effect.
In the CNS and the peripheral system, the key pain regulators are opioid receptors. There are 4 classes of opioid receptors: a) μ receptors; b) delta (δ) receptors; c) kappa (κ) receptors, and d) sigma (σ) receptors. These receptors are normally stimulated by endogenous peptides (endorphins, enkephalins and dynorphins) produced in response to noxious stimuli; endogenous enkephalins, for example, are relatively selective agonists of δ receptors. The opiod receptors can also be stimulated by drugs referred to as opioid analgesics, most of which are agonists of μ receptors (Trescot et al, 2008).
Pain management is accomplished through the use of analgesic drugs, which are the most used drugs of all classes. Three general classes of drugs are currently available for pain management: non-steriodal anti-inflammatories (NSAIDs), adjuvant analgesics, and opioids. NSAIDs act exclusively to reduce the inflammation and inflammatory mediators of pain (peripheral mechanisms) and are mainly used for mild to moderate pain indications. Adjuvant analgesics are used mainly for treatment of neuropathic pain and include various anti-depressants, anti-convulsants, neuroleptics, and corticosteroids. Centrally-acting plant opiates are the most frequently used analgesics for the relief of severe pain and include morphine and many derivatives (oxycodone, dihydrocodeine, hydrocodone, fentanyl, pentazocine, loperamide, fedotozine, naloxone, naltrexone, methyl nalozone, nalmefene, cypridime, beta funaltrexamine, naloxonazine, naltrindole, and nor-binaltorphimine). These drugs act through central pain mechanisms, where they have high selectivity for and various degree of potency on μ opioid receptors (Trescot et al, 2008).
Although opioid drugs can be very effective in pain management, they can cause several severe side effects, including:                respiratory depression that is proportional to their analgesia; this respiratory depression can be life-threatening. As a result, the range between the effective dose and a dose that produces respiratory depression is narrow. Because of this narrow therapeutic index, patients receiving opioid therapy must be closely monitored for signs of respiratory failure;        constipation in patients can be severe and may require prolonged hospitalization, or even surgical intervention;        development of physical dependence with repeated use is a characteristic feature of the opioid drugs, and the possibility of developing drug dependence is one of the major limitations of their clinical use;        cessation of opioid administration may result in a withdrawal syndrome. Symptoms of withdrawal are often the opposite of the effects achieved by the drug;        
These unwanted effects can severely limit the use of opioid drugs, and are the consequence of the drugs' selectivity to μ opioid receptors.
There is therefore a need in the art for opioid analgesics that have a diminished likelihood of side effects, for example drugs that have selective activity on δ receptors. Enkephalins are endogenous opioid receptor agonists; they are potent and preferential δ opioid receptor agonists with weak agonist effect on μ receptors (Pencheva et al, 1999). Unfortunately, these neuropeptides do not cross the blood brain barrier (BBB), undergo rapid degradation by tissue peptidases (principally amino peptidase), and have very short half-lives in the blood stream (Polt et al, 2005; Weber et al, 1991).
Many other peptides that act through mechanisms independent from opioid receptors exist (e.g., neuropeptide Y, neurotensin). However, the analgesic activity of such peptides is only exhibited when administered centrally (i.e., intra-cerebroventricularly, intra-cerebrally); no activity is observed when administered peripherally (i.e., intravenously, subcutaneously), as they do not cross the blood-brain barrier.
Therefore, there is a need for a non-invasive brain-delivery technology for centrally-acting agents. There is a further need in the art for effective agents that may be administered non-invasively. Finally, there is a need in the art for agents with improved efficacy and superior side-effect profiles to relieve pain.